| First Author | Vendrov AE | Year | 2019 |
| Journal | Redox Biol | Volume | 21 |
| Pages | 101063 | PubMed ID | 30576919 |
| Mgi Jnum | J:279190 | Mgi Id | MGI:6356492 |
| Doi | 10.1016/j.redox.2018.11.021 | Citation | Vendrov AE, et al. (2019) NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis. Redox Biol 21:101063 |
| abstractText | Increased reactive oxygen species (ROS) production and inflammation are key factors in the pathogenesis of atherosclerosis. We previously reported that NOX activator 1 (NOXA1) is the critical functional homolog of p67phox for NADPH oxidase activation in mouse vascular smooth muscle cells (VSMC). Here we investigated the effects of systemic and SMC-specific deletion of Noxa1 on VSMC phenotype during atherogenesis in mice. Neointimal hyperplasia following endovascular injury was lower in Noxa1-deficient mice versus the wild-type following endovascular injury. Noxa1 deletion in Apoe(-/-) or Ldlr(-/-) mice fed a Western diet showed 50% reduction in vascular ROS and 30% reduction in aortic atherosclerotic lesion area and aortic sinus lesion volume (P<0.01). SMC-specific deletion of Noxa1 in Apoe(-/-) mice (Noxa1(SMC-/-)/Apoe(-/-)) similarly decreased vascular ROS levels and atherosclerotic lesion size. TNFalpha-induced ROS generation, proliferation and migration were significantly attenuated in Noxa1-deficient versus wild-type VSMC. Immunofluorescence analysis of atherosclerotic lesions showed a significant decrease in cells positive for CD68 and myosin11 (22% versus 9%) and Mac3 and alpha-actin (17% versus 5%) in the Noxa1(SMC-/-)/Apoe(-/-) versus Apoe(-/-) mice. The expression of transcription factor KLF4, a modulator of VSMC phenotype, and its downstream targets - VCAM1, CCL2, and MMP2 - were significantly reduced in the lesions of Noxa1(SMC-/-)/Apoe(-/-) versus Apoe(-/-) mice as well as in oxidized phospholipids treated Noxa1(SMC-/-) versus wild-type VSMC. Our data support an important role for NOXA1-dependent NADPH oxidase activity in VSMC plasticity during restenosis and atherosclerosis, augmenting VSMC proliferation and migration and KLF4-mediated transition to macrophage-like cells, plaque inflammation, and expansion. |
